Comparison of once-daily extended-release ciprofloxacin and conventional twice-daily ciprofloxacin for the treatment of uncomplicated urinary tract infection in women

CLINICAL THERAPEUTICS®/VOL.24, NO. 12, 2002

Comparison of Once-Daily Extended-Release Ciprofloxacin and Conventional Twice-Daily Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infection in Women Dan C. Henry, Jr., MD, 1 Robert B. Bettis, MD, z Ernie Riffer, MD, 3 Daniel C. Haverstock, MS, 4 Steven F. Kowalsky, PharmD, 4 Kathryn Manning, 4 Kamal A. Hamed, AID, 4. and Deborah A. Church, MD 4 1Foothill Family Clinic, Salt Lake City, Utah, 2Edmonds Family Medicine, Edmonds, Washington, 3Central Phoenix Medical Clinic, Phoenix, Arizona, and 4pharmaceutical Division, Bayer Corporation, West Haven, Connecticut

ABSTRACT

Background: Trimethoprim/sulfamethoxazole (TMP/SMX) is currently the first choice for empiric therapy of acute uncomplicated urinary tract infection (UTI) in women. In areas where resistance to TMP/SMX is known to be high, ciprofloxacin and other fluoroquinolones are recommended as first-line choices for the empiric therapy of UTI. Objective: This study compared the efficacy and safety profile of once-daily extendedrelease ciprofloxacin 500 mg (referred to hereafter as ciprofloxacin QD) with those of conventional ciprofloxacin 250 mg BID, each administered orally for 3 days, in the treatment of uncomplicated UTI in women. Methods: In this multicenter, prospective, randomized, double-blind, double-dummy, Phase III trial, adult women with clinical signs and symptoms of acute uncomplicated UTI, pyuria, and a positive pretherapy urine culture (>105 colony-forming units/mL) received ciprofloxacin QD or ciprofloxacin BID. Bacteriologic and clinical outcomes were assessed at the test-of-cure visit (4-11 days after completion of therapy) and the late follow-up visit (25-50 days after completion of therapy). Results: The intent-to-treat population consisted of 891 patients (444 ciprofloxacin QD, 447 ciprofloxacin BID); 422 patients were evaluable for efficacy (199 ciprofloxacin Results of this study were presented in part at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27-30, 2002, San Diego, California, the 40th Annual Meeting of the Infectious Diseases Society of America, October 24-27, 2002, Chicago, Illinois, and the Annual Meeting of the American College of Clinical Pharmacy, October 20-23, 2002, Albuquerque, New Mexico. *Current affiliation: Bristol-Myers Squibb Company, Wallingford, Connecticut. Accepted for publication October 7, 2002, Printed in the USA. Reproduction in whole or part is not permitted.

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QD, 223 ciprofloxacin BID). At the testof-cure visit, bacteriologic eradication was achieved in 94.5% (188/199) of the ciprofloxacin QD group and 93.7% (209/ 223) of the ciprofloxacin BID group (95% CI,-3.5 to 5.1). Clinical cure was achieved in 95.5% (189/198) of the ciprofloxacin QD group and 92.7% (204/220) of the ciprofloxacin BID group (95% CI, -1.6 to 7.1). Bacteriologic and clinical outcomes at the late follow-up visit were consistent with the test-of-cure findings. The rate of eradication of Escherichia coli, the most prevalent organism, was >97% in each treatment group. Rates of drug-related adverse events were similar with the onceand twice-daily ciprofloxacin regimens (10% and 9%, respectively). Conclusion: Extended-release ciprofloxacin 500 mg given once daily for 3 days was as effective and well tolerated as conventional ciprofloxacin 250 mg given twice daily for 3 days in the treatment of acute uncomplicated UTI in women. Key words: ciprofloxacin, once-daily, extended-release, uncomplicated urinary tract infection. (Clin Ther. 2002;24:20882104) INTRODUCTION Urinary tract infection (UTI) is one of the most common bacterial infections encountered in the outpatient setting and is the cause of >8 million physician visits in the United States each year.l Approximately 50% of women have at least 1 episode of acute symptomatic UTI in their lifetime. 2 Most UTI episodes in young and middle-aged women are considered to be uncomplicated (ie, no fever or flank pain in a patient with an anatomically normal genitourinary tract). 2 The most common uropathogens isolated and identified

from women with acute uncomplicated episodes of UTI are members of the Enterobacteriaceae, with 80% of communityacquired infections caused by Escherichia coli.l-3 The second most common cause of UTI is Staphylococcus saprophyticus, particularly in younger women. Other common uropathogens include enterococci and gram-negative rods other than E coli, such as Klebsiella, Proteus, and Enterobacter species. Gram-positive organisms, such as group B and nonenterococcal group D streptococci, are unusual causes of UTI (1%-2%). 1-3 Selection of the optimal empiric antimicrobial agent for the treatment of symptomatic uncomplicated UTI in women continues to evolve. Important factors in the choice of empiric therapy include local patterns of antimicrobial resistance, the propensity of specific antimicrobial agents to encourage resistance or select for mutant strains, pharmacokinetic properties (eg, ability to achieve high and prolonged urinary concentrations to guarantee bactericidal activity), patient convenience (eg, frequency of dosing), tolerability, and costs. Currently, trimethoprirn/ sulfamethoxazole (TMP/SMX) is the first choice for empiric therapy of acute uncomplicated UTI in regions where rates of E coli resistance to TMP/SMX are no more than 10% to 20%. l Among other choices for empiric therapy cited in current guidelines are the fluoroquinolones, particularly in areas where resistance to TMP/SMX is known to be high (more than 10%-20%). 1,4 Since 2000, The Sanford Guide ® to Antimicrobial Therapy has recommended ciprofloxacin and other fluoroquinolones as first-line choices for the treatment of acute uncomplicated UTI because of elevated rates (> 18%) of E coli resistance to TMP/SMX. 5 2089

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Ciprofloxacin has been recognized as a safe and effective agent for the treatment of UTI for over a decade. In the United States, tablet and suspension formulations of ciprofloxacin are approved for the treatment of uncomplicated UTI at 100 or 250 mg BID for 3 days, and for mild/moderate UTI at 250 mg for 7 to 14 days. 6 A new once-daily extended-release formulation of ciprofloxacin (hereafter referred to as ciprofloxacin QD) is a bilayer tablet composed of different proportions of 2 salts of ciprofloxacin, ciprofloxacin hydrochloride and ciprofloxacin betaine. The first layer releases -35% of the dose immediately after ingestion. The second, "controlled-release" layer releases the remaining 65% of the dose at a marginally slower rate. This formulation is designed to have an absorption window such that all of the dose is released before the tablet reaches the distal region of the small intestine, thus increasing bioavailability. It is hoped that the convenience of once-daily dosing will enhance patient adherence, as adherence to the dosing regimen is an important factor in the achievement of clinical cure and reducing the potential for the emergence of resistance. The primary objective of this trial was to compare the efficacy and safety profile of extended-release ciprofloxacin 500 mg QD with those of conventional ciprofloxacin 250 mg BID, each given orally for 3 days, in the treatment of acute uncomplicated UTI in women. PATIENTS AND METHODS

Women were eligible for enrollment if they were aged between 18 and 65 years, were not pregnant, had a primary diagnosis of acute uncomplicated UTI, and could be treated on an outpatient basis. Each patient had to have >2 signs or symptoms 2090

suggestive of an acute uncomplicated UTI (ie, dysuria, frequency, urgency, suprapubic pain), with an onset of symptoms within 72 hours of enrollment. At enrollment, a clean-catch midstream urine specimen was obtained from each patient. A positive culture was defined as isolation of a uropathogen in quantities _>105 colony-forming units (CFU)/mL urine, and pyuria was defined as >10 leukocytes/ mm 3 in unspun urine examined in a counting chamber. Each patient gave written informed consent before participation. The primary exclusion criteria were asymptomatic infection (bacteriuria); suspicion of complicated UTI (eg, presence of fever, flank pain, known urologic structural abnormality); symptoms of a UTI within the past 4 weeks; _>3 previous UTIs within the past year; evidence of predisposing factors to UTI (eg, calculi, stricture, primary renal disease, neurogenic bladder); history of fluoroquinolone hypersensitivity; history of tendinopathy associated with use of fluoroquinolones; neutrophil count <1000 cells/mm s, CD4+ count <200 cells/mm 3, or other conditions associated with significant immunosuppression; use of a systemic antimicrobial agent within 48 hours before enrollment; ingestion of sucralfate or a cation-containing antacid <6 hours before or <2 hours after administration of study drug; serum creatinine level _>3.0 mg/dL or creatinine clearance <30 mL per rain/1.73 m2; and liver impairment (ie, baseline aspartate aminotransferase, alanine aminotransferase, and/or total bilirubin >3 times the upper limit of normal).

Study Design and Treatments This was a prospective, double-blind, double-dummy, Phase III trial conducted at 58 medical centers in the United States.

D.C. HENRY, JR., ET AL.

A computer-generated randomization code (Bayer Corporation, West Haven, Connecticut) was used to assign patients in a 1:1 ratio to receive extended-release ciprofloxacin 500 mg QD or conventional ciprofloxacin 250 mg BID, each administered orally for 3 days. The protocol received approval from a central institutional review board. Both ciprofloxacin formulations were provided by the Pharmaceutical Division of Bayer Corporation. Medications were supplied in 2 bottles for blinding purposes. Bottle 1 contained extended-release ciprofloxacin 500 mg or placebo, and bottle 2 contained ciprofloxacin 250 mg or placebo. Placebo tablets were identical in appearance to the corresponding tablets of active drug. Each day for 3 days, patients received 2 tablets (1 from each bottle) for the morning dose and 1 tablet (from bottle 2) for the evening dose. All doses of study medication were taken with _>120 mL water with or without food. Concomitant antimicrobial agents were not permitted at any time during the activetreatment period through the late followup visit. Use of phenazopyridine or an alternative urinary analgesic was allowed. Patients were assessed 3 times during the study: at the pretreatment visit, the test-of-cure visit (4-11 days after completion of therapy), and the late follow-up visit (25-50 days after completion of therapy). Antimicrobial effectiveness was assessed in terms of conventional clinical and laboratory determinations, including serial urine cultures from clean-catch midstream specimens. Bacteriologic response at the test-of-cure visit was the primary efficacy variable. Identification of causative organisms and susceptibility testing were performed by a central laboratory (Covance Central Laboratory Services, Inc.,

Indianapolis, Indiana) in accordance with National Committee for Clinical Laboratory Standards (NCCLS) guidelines. 7,8 Tolerability was assessed in the intentto-treat population, which included all patients who received study drug for any length of time. Tolerability was monitored by clinical observation, adverse-event monitoring, measurement of vital signs, urinalysis, and routine serum chemistry and hematologic testing. Adverse events were classified by the investigator according to their severity (mild, moderate, or severe), relationship to study drug (probable, possible, unlikely, or none), and seriousness (events that were lifethreatening, fatal, required hospitalization, resulted in disability, or otherwise jeopardized the patient). Adverse events were recorded through the test-of-cure visit, and serious adverse events were recorded through the late follow-up visit. Efficacy Assessment

For a course of therapy to be judged valid for assessment of drug efficacy, the following criteria must have been satisfied: (1) diagnosis of UTI was confirmed by clinical signs and symptoms; (2) culture from a pretreatment clean-catch midstream urine specimen was positive for an infecting organism, with a count _>105 CFU/mL; (3) significant pyuria was present; (4) study drug was administered for a minimum of 2 days (4 doses) if the clinical outcome was failure at the test-of-cure visit, or a minimum of 3 days (_>5 doses or 8 tablets) if the clinical outcome was cure; (5) patients received no other concomitant antimicrobial agent with activity against the causative organism; (6) no protocol violations occurred; and (7) study blinding was not broken. 2091

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The bacteriologic response was assessed based on a comparison of the results of urine culture performed before treatment and at the test-of-cure and late follow-up visits. At the test-of-cure visit, bacteriologic outcomes were categorized as eradication (<10 4 CFU/mL of original uropathogen), persistence (_>104 CFU/mL of original uropathogen), superinfection (>105 CFU/mL of a uropathogen other than the original pathogen at any time during active therapy), new infection (>105 CFU/mL of a uropathogen other than the original pathogen at any time after the end of active therapy), or indeterminate (not evaluable for any reason, such as no posttreatment culture). At the late follow-up visit, bacteriologic outcomes were categorized as continued eradication ( < 1 0 4 CFU/mL of original uropathogen at the test-of-cure and late follow-up visits), persistence (as before), superinfection (as before), recurrence (<104 CFU/mL of original organism at the test-of-cure visit, but >104 CFU/mL of same organism before or at the late follow-up visit), new infection (as before), or indeterminate (as before). The clinical outcome was evaluated based on serial assessments of the effect of therapy on the signs and symptoms of UTI (dysuria, frequency, urgency, and suprapubic pain). At the test-of-cure visit, the clinical response was categorized as cure (disappearance of or improvement in signs and symptoms of the infection such that additional antimicrobial therapy was not required), failure (no apparent response to therapy, persistence of signs and symptoms of infection, reappearance of signs and symptoms at or before the testof-cure visit, or use of additional antimicrobial therapy for the current infection), or indeterminate (not evaluable). At the late follow-up visit, the clinical response 2092

was classified as continued cure (continued absence of or improvement in all signs and symptoms of infection such that additional antimicrobial therapy was not needed), failure (patients with a response of failure at the test-of-cure visit carried forward), relapse (reappearance of signs and symptoms of original infection requiring antimicrobial therapy in a patient with a response of cure at the test-of-cure visit), or indeterminate (not evaluable). In addition to assessment of the bacteriologic and clinical responses in all patients who were valid for efficacy analysis, an intent-to-treat analysis was conducted including all patients who received study drug.

Pharmacokinetic Assessment On study days 2 and 3, blood and urine samples were obtained from a subset of patients from 10 of the participating medical centers for determination of ciprofloxacin concentrations. Samples were collected at or near the end of the dosing interval (ie, between 20 and 24 hours after dosing of ciprofloxacin QD and between 8 and 12 hours after dosing of ciprofloxacin BID) for comparison of trough concentrations. A 7-mL blood sample was collected in a chilled tube; within 30 minutes, the sample was centrifuged at 1500g for 10 minutes to separate the plasma. The plasma was transferred to a polypropylene tube and stored at -20°C until analyzed. A 10-mL urine sample was collected and stored in a polypropylene vial at -20°C. The Bioanalytical Laboratory at Bayer Corporation analyzed plasma and urine samples for ciprofloxacin concentrations using a validated high-performance liquid chromatography (HPLC) assay. In brief,

D.C. HENRY, JR., ET AL.

the HPLC procedure used protein precipitation and enhanced fluorescence detection after postcolumn ultraviolet reaction. 9 The calibration of ciprofloxacin in plasma ranged from 0.05 to 7.5 p~g/mL. The intraday precision (% coefficient of variation [CV]) ranged from 0.4% to 6.1%, and the interday precision (% CV) ranged from 1.4% to 4.1% for all quality control samples and the lower quantitation limit calibration standard. Intraday accuracy ranged from 96.0% to 103.13%, and interday accuracy ranged from 98.0% to 102.09%. The calibration of ciprofloxacin in urine ranged from 0.1 to 20 mg/L; interday precision ranged from 0.4% to 6.1%. Intraday and interday accuracy ranged from 96.0% to 103.1%.

Statistical Analysis To determine whether ciprofloxacin QD was noninferior to ciprofloxacin BID based on eradication rates, a null hypothesis was constructed specifying that the eradication rate in the ciprofloxacin BID group was at least 10% higher than that in the ciprofloxacin QD group. If this null hypothesis could be rejected, then it could be concluded that ciprofloxacin QD was noninferior to ciprofloxacin BID based on eradication rates using a A of 10% (ie, difference in true failure rates). With 422 patients valid for efficacy and a maximum allowable A of 10%, this study had >90% power to detect noninferiority in eradication rates between ciprofloxacin QD and ciprofloxacin BID (t~ = 0.25, 1-sided). Categoric baseline medical variables were analyzed using chi-square tests. For continuous variables, a 1-way analysis of variance model was used to compare the 2 treatment groups. Comparisons of the incidence of adverse events were descrip-

tive. All adverse events and drug-related adverse events were tabulated by type (according to the World Health Organization Coding System for Adverse Reaction Terminology) and frequency. Plasma and urine ciprofloxacin concentrations were analyzed using descriptive statistics. For the bacteriologic and clinical responses at the test-of-cure and late followup visits, the differences in eradication and cure rates were estimated using a 95% CI generated by a Mantel-Haenszel weighting procedure. The weights used to generate the CI were based on the sample size for the study center. In terms of eradication rates, noninferiority was defined statistically as a > - 1 0 % lower limit of the 2-sided 95% CI for the difference between treatment groups. Similar statistical analyses were performed on both efficacy variables for the intent-to-treat population. RESULTS

PafientPopulation The intent-to-treat population consisted of 891 patients (444 ciprofloxacin QD, 447 ciprofloxacin BID), of whom 422 were evaluable for efficacy (199 ciprofloxacin QD, 223 ciprofloxacin BID). Of the 469 patients not valid for efficacy, 90% (421) were excluded because no causative organism was isolated in sufficient quantity (ie, >105 CFU/mL) before treatment. Other reasons for exclusion included invalid posttherapy culture (15 ciprofloxacin QD, 12 ciprofloxacin BID), protocol violation (6 ciprofloxacin QD, 9 ciprofloxacin BID), use of concomitant antimicrobial agent (2 ciprofloxacin QD, 1 ciprofloxacin BID), noncompliance (1 ciprofloxacin QD, 1 ciprofloxacin BID), 2093

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and loss to follow-up (1 ciprofloxacin BID). Twenty-four patients were prematurely discontinued from the study (13 ciprofloxacin QD, 11 ciprofloxacin BID). The reasons for premature discontinuation were loss to follow-up (6 ciprofloxacin QD, 7 ciprofloxacin BID), adverse event (2 ciprofloxacin QD, 2 ciprofloxacin BID), therapeutic failure (1 ciprofloxacin QD, 1 ciprofloxacin BID), noncompliance (2 ciproftoxacin QD), consent withdrawn (2 ciprofloxacin QD), and protocol violation (1 ciprofloxacin BID). The baseline demographic and medical characteristics of efficacy-valid patients are summarized in Table I. There were no statistically significant differences between the 2 treatment groups with respect to age (mean age, 35 years), health status, or presence of concomitant diseases. More than two thirds of patients reported no history of a UTI within the past year. The majority of patients reported having symptoms of the current UTI for 2 to 3 days. The 2 treatment groups were also well balanced with respect to distribution of symptoms and symptom severity. Overall, urinary frequency was the most common symptom (97.6%), followed by urgency (95.0%), dysuria (89.6%), and suprapubic pain (76.1%). Most patients reported that the intensity of their symptoms was mild to moderate, although urinary urgency was severe in 37.4% of patients. The baseline demographic and medical characteristics of the intent-to-treat population were similarly balanced (Table I).

col) from each efficacy-valid patient. For the efficacy-valid population, 204 organisms were isolated from 199 patients who received ciprofloxacin QD, and 239 organisms were isolated from 223 patients receiving ciprofloxacin BID. The most common pretherapy uropathogens were E coli (160 ciprofloxacin QD, 181 ciprofloxacin BID), Enterococcus faecalis (11 ciprofloxacin QD, 21 ciprofloxacin BID), Klebsiella pneumoniae (9 ciprofloxacin QD, 14 ciprofloxacin BID), Proteus mirabilis (12 ciprofloxacin QD, 7 ciprofloxacin BID), and S saprophyticus (6 ciprofloxacin QD, 7 ciprofloxacin BID). With the exception of 5 isolates, all pretherapy isolates were found to be susceptible to ciprofloxacin (minimum inhibitory concentration [MIC] <1 rag/L). One isolate of E coli from the ciprofloxacin QD group was resistant to ciprofloxacin (MIC 16 mg/L), whereas a second E coli isolate from the ciprofloxacin BID group had intermediate susceptibility (MIC 2 mg/L). One isolate of S saprophyticus from the ciprofloxacin QD group had intermediate susceptibility to ciprofloxacin (MIC 2 mg/L). Two isolates of E faecalis (1 from each treatment group) had intermediate susceptibility to ciprofloxacin (MIC 2 mg/L). It should be noted that resistance was documented using standard NCCLS breakpoints, which are based on achievable plasma concentrations and not urinary levels. As such, some uropathogens categorized as resistant to ciprofloxacin would be expected to be eradicated successfully.

Pretherapy Uropathogens and Susceptibility

Bacteriologic Outcomes

One or 2 causative organisms (but not >2) were isolated and identified in sufficient numbers (as specified by the proto-

At the test-of-cure visit, bacteriologic eradication was achieved in 94.5% (188/ 199) of the ciprofloxacin QD group and

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Table I. D e m o g r a p h i c and baseline medical characteristics of female patients with an acute u n c o m p l i c a t e d urinary tract infection (UTI). Efficacy-Valid Population

Intent-to-Treat Population

Ciprofloxacin 500 mg QD x3d (n = 199)

Ciprofloxacin 250 mg BID x3d (n = 223)

Ciprofloxacin 500 mg QD x3d (n = 444)

Ciprofloxacin 250 mg BID x3d (n = 447)

34.3 (11.7) 18-64

35.1 (12.7) 18~55

35.2 (12.6) 18-79

34.8 (12.6) 18-76

Race, no. (%)* White Hispanic Black Asian Native American

154 (77.4) 21 (10.6) 17 (8.5) 5 (2.5) 1 (0.5)

179 (80.3) 20 (9.0) 18 (8.1) 5 (2.2) 1 (0.4)

350 39 43 9 2

No. of UTI episodes in past year, no. (%)t 0 1 2 3

133 (66.8) 51 (25.6) 15 (7.5) -

155 (69.5) 51 (22.9) 17 (7.6) -

280 (63.1) 122 (27.5) 41 (9.2) 1 (0.2)

284 117 43 3

(63.5) (26.2) (9.6) (0.7)

Reported symptoms of current UTI, no. (%)* Frequency Urgency Dysuria Suprapubic pain

193 191 180 152

(97.0) (96.0) (90.5) (76.4)

219 210 198 169

(98.2) (94.2) (88.8) (75.8)

427 419 395 327

(96.2) (94.4) (89.0) (73.6)

435 416 390 337

(97.3) (93.1) (87.2) (75.4)

22 92 76 9

(11.1) (46.2) (38.2) (4.5)

37 (16.6) 97 (43.5) 79 (35.4) 10 (4.5)

66 189 167 22

(14.9) (42.6) (37.6) (5.0)

69 (15.4) 190 (42.5) 171 (38.3) 17 (3.8)

196 (98.5)

218 (97.8)

430 (96.8)

432 (96.6)

Variable Age, y Mean (SD) Range

Duration of symptoms of current UTI, no. (%)* 1 day 2 days 3 days >4 days General health excellent/good, no. (%)

(78.8) (8.8) (9.7) (2.0) (0.5)

358 (80.1) 38 (8.5) 37 (8.3) 12 (2.7) 2 (0.4)

None of the differences between treatment groups were statistically significant. *Information missing for 1 patient in the ciprofloxacin 500 mg QD group. tpercentages may not total 100 due to rounding error.

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93.7% (209/223) of the ciprofloxacin BID group (Table II). These results disproved the null hypothesis and demonstrated that ciprofloxacin QD was statistically noninferior to ciprofloxacin BID (95% CI, -3.5 to 5.1). Among patients in whom treatment was not a bacteriologic success, a new infection was recorded in 4 ciprofloxacin QD patients (1 of these patients also had persistence of the original pathogen) and 3 ciprofloxacin BID patients; all new infections were caused by E faecalis. Persistence of the original pathogen was recorded in 19 patients (8 ciprofloxacin QD, 11 ciprofloxacin BID). For E coli, the most prevalent organism, >97% of isolates were eradicated in each treatment group. Eradication rates of the most common isolates are summarized in Table III. At the late follow-up assessment, continued eradication was reported for 85.8% (151/176) of the ciprofloxacin QD group

and 81.3% (165/203) of the ciprofloxacin BID group (95% CI, -1.9 to 12.2) (Table II). Rates of continued eradication of E coli, P mirabilis, and S saprophyticus at this assessment continued to be high in both treatment groups. However, 31 patients had a recurrent infection (14 ciprofloxacin QD, 17 ciprofloxacin BID). These recurrent infections were caused by E coli (12 ciprofloxacin QD, 9 ciprofloxacin BID), K pneumoniae (1 ciprofloxacin QD, 1 ciprofloxacin BID), Efaecalis (6 ciprofloxacin BID), Enterobacter aerogenes (1 ciprofloxacin QD), S saprophyticus (1 ciprofloxacin BID), and Citrobacter (l ciprofloxacin BID); 2 pathogens were isolated from 1 patient in the ciprofloxacin BID group. Organisms that were not present at the test-of-cure visit but appeared before or at the late followup visit were isolated from 3 and 10 patients in the ciprofloxacin QD and BID groups, respectively. The majority of

Table II. Bacteriologic response (no. [%]) at the test-of-cure (4-11 days after completion of therapy) and late follow-up (25-50 days after completion of therapy) visits in the efficacy-valid population. Ciprofloxacin 500 mg QD x3d

Ciprofloxacin 250 mg BID x3d

Test-of-cure visit Eradication Persistence New infection

(n = 199) 188 (94.5) 8 (4.0) 3 (1.5)*

(n = 223) 209 (93.7) 11 (4.9) 3 (1.3)

Late follow-up visit + Continued eradication Eradication with recurrence Persistence New infection

(n = 176) 151 (85.8) 14 (8.0) 8 (4.5) 3 (1.7)

(n = 203) 165 (81.3) 17 (8.4) 11 (5.4) 10 (4.9)

Visit/Response

*An additional patient who had persistence as well as a new infection is listed only under persistence. qndeterminate responses were excluded. 2096

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Table III. Bacteriologic eradication rates by pathogen (n/N [%]) at the test-of-cure visit (4-11 days after completion of therapy) in the efficacy-valid population.

Organism

Ciprofloxacin 500 mg QD x3d

Ciprofloxacin 250 mg BID x3d

Escherichia coli Enterococcusfaecalis Klebsiella pneumoniae Proteus mirabilis Staphylococcus saprophyticus Miscellaneous*

156/160 (97.5) 10/11 (90.9) 719 (77.8) 11/ 12 (91.7) 5/6 (83.3) 6/6 (100)

176/181 17/21 11/14 7/7 7/7 9/9

(97.2) (81.0) (78.6) (100) (100) (100)

*Miscellaneous organisms included Proteus vulgaris (1), Enterobacter species (4), and Stenotrophomonas maltophilia (1) for ciprofloxacin QD and Klebsiella species (2), Enterobacter species (5), and Citrobacter species (2) for ciprofloxacin BID.

these new infections were caused by E faecalis. It is noteworthy that emergence of resistance to ciprofloxacin during or after therapy was rare in this study. In the 50 women who had persistent organisms at the test-of-cure visit or recurrent organisms at the late follow-up visit, as well as pretherapy and posttherapy MIC data, only 1 isolate (E coli) had become resistant to ciprofloxacin. The original MIC for the E coli isolate was 0.03 mg/L, which had increased to 4 mg/L at the late followup visit. The patient, who received ciprofloxacin BID, was considered to be clinically cured with bacteriologic eradication at the test-of-cure visit, but was categorized as having bacteriologic relapse with continued clinical cure at the late followup visit. Clinical Outcomes

The results of the assessment of clinical response were consistent with those of the assessment of bacteriologic response in

that ciprofloxacin QD was noninferior to ciprofloxacin BID. Although the difference was not statistically significant, at the test-of-cure visit the ciprofloxacin QD group had a slightly higher clinical success rate than the ciprofloxacin BID group (95.5% and 92.7%, respectively; 95% CI, -1.6 to 7.1 ) (Table IV). Rates of continued clinical cure at the late follow-up visit were 89.0% ( 161 / 181 ) for ciprofloxacin QD and 86.6% (187/216) for ciprofloxacin BID (95% CI,-3.1 to 8.8). Approximately 13% of patients in both treatment groups used an antimicrobial agent after the completion of study drug. Eleven (6.1%) ciprofloxacin QD patients and 13 (6.0%) ciprofloxacin BID patients had a relapse 1 to 2 months after completion of study drug. Bacteriologic eradication and clinical cure were highly correlated: 97.3% (182/187) of the ciprofloxacin QD group and 95.1% (196/206) of the ciprofloxacin BID group were classified as bacteriologic and clinical successes. In contrast, bacteriologic persistence or development of a new infection was not highly predictive of 2097

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Table IV. Clinical outcomes (n/N [%]) at the test-of-cure (4-11 days after completion of therapy) and late follow-up (25-50 days after completion of therapy) visits.* Efficacy-Valid Population Ciprofloxacin 250 mg BID x3d

Intent-to-Treat Population

Visit/Response

Ciprofloxacin 500 mg QD x3d

Ciprofloxacin 500 mg QD x3d

Ciprofloxacin 250 mg BID x3d

Test-of-cure visit Cure Failure

189/198 (95.5) 204/220 (92.7) 9/198 (4.5) 16/220(7.3)

Late follow-up visit Continued cure Failure t Relapse

161/181 (89.0) 187/216 (86.6) 335/403 (83.1) 357/416(85.8) 9/181 (5.0) 16/216(7.4) 43/403(10.7) 30/416 (7.2) 11/181 (6.1) 13/216(6.0) 25/403(6.2) 29/416 (7.0)

382/425 (89.9) 395/425 (92.9) 43/425 (10.1) 30/425 (7.1)

*Indeterminateand missing responses are excluded. +Includes only those patients in whom therapy was considered a failure at the test-of-curevisit; these observations were carried forward. clinical failure: among patients who had a bacteriologic response of failure, only 36.4% (4/11) of the ciprofloxacin QD group and 42.9% (6/14) of the ciprofloxacin BID group were also clinical failures. In addition, 15 patients with a bacteriologic response of eradication had a clinical response of failure (5 ciprofloxacin QD, 10 ciprofloxacin BID); 10 patients with a bacteriologic response of persistence had a clinical response of cure (5 ciprofloxacin QD, 5 ciprofloxacin BID); and 5 patients developed a new infection but had a clinical response of cure (2 ciprofloxacin QD, 3 ciprofloxacin BID).

Plasma~Urine Ciprofloxacin Concentrations

Plasma and urine samples were collected from 71 patients between 20 and 24 hours (mean, 22 hours) after the previous day's morning dose on day 2 or 3 of therapy. The 2098

mean plasma ciprofloxacin concentration based on the 23 blood samples collected from recipients of ciprofloxacin QD was 0.13 mg/L (range, <0.05-1.6 rag/L). The mean plasma ciprofloxacin concentration in the 22 samples collected from the ciprofloxacin BID group was 0.20 mg/L (range, <0.05-0.6 mg/L). The mean urine concentration of ciprofloxacin in samples obtained from 24 patients receiving ciprofloxacin QD was 37 mg/L (range, 3.6-177.2 rag/L), compared with 65 mg/L (range, 6.6-308.8 mg/L) in samples obtained from 21 patients receiving ciprofloxacin BID. There was no apparent relationship between these plasma or urine ciprofloxacin concentrations toward the end of the dosing interval and the bacteriologic or clinical response.

Tolerability Eight hundred ninety-one patients were evaluable for drug tolerability. Two

D.C. HENRY, JR., ET AL.

patients in both treatment groups experienced >1 adverse event resulting in premature discontinuation. In the ciprofloxacin QD group, the adverse events leading to discontinuation were abdominal pain, back pain, nausea, vomiting, and dysuria (reported on day 3) in 1 patient, and prutitus and maculopapular rash (reported on day 2) in 1 patient. In the ciprofloxacin BID group, 1 patient discontinued study drug due to nausea reported on day 2, and 1 patient was withdrawn because of pyelonephritis. All these events resolved or improved. At least 1 treatment-emergent adverse event was reported in 27.3% (121/444) of patients who received >1 dose of ciprofloxacin QD and in 23.5% (105/447) of patients who received >1 dose of ciprofloxacin BID (Table V). Most (199/226 [88.1%]) adverse events were mild or moderate in both groups. Drug-related adverse events were reported by 46 (10.4%) patients in the ciprofloxacin QD group and 41 (9.2%) in the ciprofloxacin BID group. Ten drug-related adverse events were categorized as severe (3 ciprofloxa-

cin QD, 7 ciprofloxacin BID); these were headache (5), nausea (2), diarrhea (1), vaginitis (1), and vaginal moniliasis (1). The types of drug-related adverse events reported were similar between treatment groups (Table V). There were no serious drug-related adverse events in either group. DISCUSSION Antimicrobial choices for the treatment of UTI in women have been studied extensively, with several agents demonstrating good to excellent efficacy when prescribed at appropriate doses, l For at least a decade, a short course of therapy (3 days) has been recommended for acute episodes of uncomplicated UTI in young women. 1-3 Since the early 1990s, TMP/SMX has been the preferred antimicrobial agent for the empiric treatment of these infections in women. 1 However, the incidence of resistance to TMP/SMX has risen dramatically, l°-12 A longitudinal study by Gupta et al l° reported that TMP/SMX resistance in urinary isolates of E coli ob-

Table V. Incidence of adverse events (no. [%]) in the intent-to-treat population.

Adverse Event At least 1 treatment-emergent event At least 1 drug-related event Specific drug-related events* Headache Nausea Vaginal moniliasis Vaginitis

Ciprofloxacin 500 mg QD ×3d (n = 444)

Ciprofloxacin 250 mg BID ×3d (n = 447)

121 (27.3) 46 (10.4)

105 (23.5) 41 (9.2)

7 (1.6) 12 (2.7) 4 (0.9) 4 (0.9)

3 (0.7) 4 (0.9) 10 (2.2) 7 (1.6)

*Includes only events occurring in >2% of patients in either treatment group. 2099

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tained from women with uncomplicated cystitis had doubled from 9% in 1992 to 18% in 1996. Subsequent studies conducted in the United States have reported that resistance to TMP/SMX varies by region, with rates ranging from 10% to 22%. 11,12 These findings are important, particularly as studies have shown that patients infected with TMP/SMX-resistant E coli are more likely to experience failure of TMP/SMX therapy (30%-50% failure rates), 13-17 In these studies, ciprofloxacin was uniformly effective against isolates of E coli that demonstrated TMP/SMX resistance. Thus far, ciprofloxacin has been associated with low (<3%) rates of E coIi uropathogen resistance in the United States, 1°'11,18 making it a potentially attractive treatment option. It should be noted that emerging quinolone resistance has been reported in parts of Europe and Latin America, 19-23 where antibiotics are available over the counter in some countries, emphasizing the need for responsible prescription of antimicrobial agents in this country. The large, multicenter, prospective study described here enrolled 891 young women with an acute uncomplicated UTI, of whom 422 were evaluable for efficacy. At a dosage of 500 mg QD for 3 days, extended-release ciprofloxacin was an effective antibacterial agent in these patients. In terms of the primary efficacy measure, bacteriologic eradication at the test-of-cure visit, similar rates (-94%) were achieved in both treatment groups. In addition, clinical cure rates at the test-of-cure visit were similar in those receiving ciprofloxacin QD (95.5%) and those receiving ciprofloxacin BID (92.7%). The effectiveness of ciprofloxacin QD, both bacteriologically and clinically, was maintained through the late follow-up visit, which took 2100

place 25 to 50 days after the end of therapy. The bacteriologic eradication rate with ciprofloxacin QD was comparable to rates in earlier controlled clinical studies, 16'24'25 in which eradication rates after a 3-day course of conventional ciprofloxacin BID ranged from 88% to 94%. It is important to note that in actual clinical practice, culture and susceptibility testing are not often performed in young to middle-aged women with acute uncomplicated UTI. Accordingly, many women who do not have an infection receive inappropriate antimicrobial therapy when their symptoms would have resolved without a prescription. Therefore, for comparison of the efficacy of the 2 ciprofloxacin formulations in the present trial, it was essential to include only women with sufficient urine counts of a documented pretherapy pathogen. When empiric antimicrobial therapy is not followed up with adequate culture and susceptibility testing, physicians may gain a false sense of the effectiveness of an antimicrobial agent. For this reason, welldesigned clinical trials are needed to investigate and discern differences in effectiveness between treatments. Antimicrobial agents used to treat UTI should have good in vitro activity against the expected pathogens and should achieve high and prolonged urinary concentrations. Also, drugs that exert a postantibiotic effect against key uropathogens may have enhanced overall effectiveness. Ciprofloxacin has excellent in vitro activity against E coli, the most prevalent uropathogen, and against other commonly isolated uropathogens (eg, S saprophyticus, Klebsiella species, P mirabilis). 26 The pharmacokinetic profile of ciprofloxacin after twice-daily oral administration is well established. Specif-

D.C. HENRY, JR., ET AL.

ically, ciprofloxacin is primarily excreted renally by both active tubular secretion and passive glomerular filtration, resulting in extremely high (>81 mg/L 12 hours after dosing) and bactericidal urine concentrations. 27 It has been shown to exhibit a postantibiotic effect against E coli for - 4 hours after discontinuation. 28 In addition to the greater convenience of oncedaily dosing, the ciprofloxacin QD formulation has potential pharmacokinetic advantages. Considerably greater urine ciprofloxacin concentrations have been reported in the first 12 hours after administration of the ciprofloxacin QD formulation compared with the conventional BID formulation. 29 Specifically, mean urine concentrations after a single 500mg dose of the extended-release formulation were 338 mg/L from 0 to 4 hours after dosing, 137 mg/L from 4 to 8 hours, and 57 mg/L from 8 to 12 hours. Respective concentrations after a single 250-mg standard tablet were 161, 65, and 27 mg/L. At steady-state, mean urine concentrations were also much greater after administration of the extended-release formulation compared with the standard tablet formulation (eg, 368 vs 196 mg/L 0-4 hours after dosing). These observations suggest improved urine bactericidal activity with the extended-release formulation, 3° although the clinical significance of higher urinary concentrations (eg, whether they lead to faster symptom resolution) remains to be determined. The present study found that urine concentrations of ciprofloxacin measured 0 to 4 hours before the next dose (ie, 20-24 hours after dosing) were sufficiently high to kill typical community-acquired uropathogens. After administration of ciprofloxacin 500 mg QD, mean urine concentrations (37 mg/L) at the end of the 24-hour dosing interval

were well above the MIC for E coli (0.03 mg/L) 26 in all patients. The results of this trial add to the evidence that ciprofloxacin is a welltolerated fluoroquinolone with a good safety profile. The new once-daily formulation exhibited a safety profile similar to that of ciprofloxacin BID. The incidence of adverse events was similar between treatment groups, and only 2 (<1%) patients in each treatment group discontinued therapy prematurely because of an adverse event. Few drug-related adverse events were considered severe, and rates of such events were comparable between the 2 ciprofloxacin groups. CONCLUSIONS In this study, the efficacy and tolerability of extended-release ciprofloxacin 500 mg QD administered for 3 days to women with acute uncomplicated UTI were comparable to those of conventional ciprofloxacin 250 mg BID administered for 3 days. The new ciprofloxacin formulation, which offers the convenience of once-daily dosing and a side-effect profile comparable to that of ciprofloxacin BID, could prove to be an effective first-line option for the empiric therapy of acute uncomplicated UTI in women. Based on current treatment guidelines, ciprofloxacin or another alternative antimicrobial agent should be considered for the treatment of an acute uncomplicated UTI when resistance to TMP/SMX is known or suspected to be high. ACKNOWLEDGMENTS The authors thank Teresa Tartaglione, PharmD, Amy Plofker, and Cindy Duval Jobe, PhD, for their critical review and contributions to the manuscript. 2101

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course ciprofloxacin, ofloxacin, or trimethoprim/sulfamethoxazole for the treatment of acute urinary tract infection in women. Am J Med. 1999;106:292-299. 17. Noskin GA, Zembower T, Chmielewski J, et al. Disappearance of the "uncomplicated" urinary tract infection. Clin Drug Invest. 2001;21(Suppl 1):13-20. 18. Karlowsky JA, Kelly LJ, Thornsberry C, et al. Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States. Antimicrob Agents Chemother. 2002;46:2540-2545. 19. Goettsch W, van Pelt W, Nagelkerke N, et al. Increasing resistance to fluoroquinolones in Escherichia coli from urinary tract infections in the Netherlands. J Antimicrob Chemother. 2000;46:223-228. 20. Kahlmeter G. The ECO*SENS Project: A prospective, multinational, multicentre epidemiological survey of the prevalence and antimicrobial susceptibility of urinary tract pathogens--interim report. J Antimicrob Chemother. 2000;46(Suppl 1): 15-22. 21. Felmingham D, Arakawa S. Resistance among urinary tract pathogens: Experience outside the USA. Clin Drug Invest. 2001;21(Suppl 1):7-11. 22. Farra A, Skoog G, Wallen L, et al. Antibiotic use and Escherichia coli resistance trends for quinolones and cotrimoxazole in Sweden. Scand J Infect Dis. 2002;34: 449-455. 23. Gales AC, Jones RN, Gordon KA, et al. Activity and spectrum of 22 antimicrobial agents tested against urinary tract infection pathogens in hospitalized patients in Latin America: Report from the second year of the SENTRY Antimicrobial Sur-

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30. Naber KG, Theuretzbacher U, MonevaKoucheva G, Stass H. Urinary excretion and bactericidal activity of intravenous

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Address correspondence to: Dan C. Henry, Jr., MD, Foothill Family Clinic, 2295 Foothill Drive, Salt Lake City, UT 84109. E-mail: henryl @sisna.com

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